The central tenant of this proposal is that mesenchymal cells are necessary participants in tissue development, maintenance and repair and will be required for realization of the full potential of reprogrammed cells in regenerative medicine. Efforts to exploit the advance of cell reprogramming will depend upon in-depth understanding of how cell state is specified, how the cells organize into complex patterns and how heterotypic cells interrelate during times of physiologic stress. A cell autonomous perspective on these processes is inadequate and can be complemented by full elucidation of the contributory role tissue specific mesenchymal cells play. Based on lessons from development, it is clear that mesenchymal cells are fundamental for establishing the organization of a tissue, altering the proliferation, differentiation and patterning of specific cell types. Yet mesenchymal populations remain enigmatic in terms of their complexity, their lineage relationships and the regulatory pathways that mediate their functions. This proposal seeks to address this deficiency by assembling a group of investigators with complementary strengths who have a record of highly productive and collaborative science. The following specific aims will be addressed: 1. Define mesenchymal lineages comprising organ stroma in marrow, lung and heart generating molecular signatures of specific mesenchymal cell states and using these to develop methods for the prospective isolation of mesenchymal subsets. 2. Assess the lineage relationships and function of specific mesenchymal subpopulations in marrow, lung and heart in vivo. 3. Interact with other Consortium participants emphasizing tissue specific progenitors to test how specific mesenchymal subpopulations alter the differentiation and self-renewal of lung, heart and marrow progenitor cells and enhance their ability to engraft in injured tissues. Successful accomplishment of these aims will provide a complement to progenitor focused aspects of the Consortium and thereby enable a tissue-based approach to regenerative medicine.